In this issue of ONCOLOGY, Waner and Suen review their classification and treatment of congenital vascular lesions of the face and neck region. Certainly, from a therapeutic perspective, this is a nice summary of the state of the art of treatment modalities. The uses of surgery, phototherapy, laser ablation, and other modalities (eg, intralesional injection, steroids, embolization, and interferon) are summarized adequately for the general practitioner. The main focus is on cosmesis, with only little attention paid to the life-threatening conditions of intracranial vascular malformations (Figure 1) and massive head and neck vascular lesions (Figure 2).
Proposed Classification Fails to Elucidate Real Issues
The authors state that the lack of a true therapeutic protocol stems from the absence of an accepted classification of these lesions and a poor understanding of their behavior. To counter this paucity of information, they propose a classification that subdivides all lesions into hemangiomas (proliferative lesions) and malformations (static vascular lesions). This classification is based on vague, imprecise criteria, such as light microscopic histologic findings (eg, endothelial proliferation, perivascular stroma, mast cells), lesional behavior (proliferative, involutional, or persistent), natural history (involution during the neonatal period or 4 to 6 years postpartum, or no involution), and location (cutaneous, dermal, deep, or compound).
Interestingly enough, the use of hereditary or genetic factors, a major issue with many of these lesions (eg, hereditary telangiectasia) and differentiation from benign vascular tumors that involute (angiofibromata) are not enumerated or defined in this system . Thus, this classification is a personal amalgam based on the existing literature that does not contribute to the true understanding of the real issues. Furthermore, based on these vague classes, the lesions are treated, for the most part, with ablative and cosmetic measures that have very little to do with their classification. Rather, the therapeutic measures have more to do with the location of and access to the lesions. To those who are more scientifically rigorous or need information in greater depth and detail, this review is somewhat simplistic and naive.
Angiogenesis Plays a Key Role
The growth of new blood vessels (angiogenesis) plays a key role in this group of vascular lesions. Angiogenesis is also important in development (embryogenesis), wound healing, inflammation, neural regeneration, endocrinopathies (diabetic retinopathy), collagen vascular diseases (rheumatoid arthritis), periodontal disease, and cancer [2-12]. These are just a few areas in which an understanding of molecular biology has led to the identification of molecules that regulate angiogenesis. Today, there is much interest in the development of therapeutic agents that inhibit angiogenesis through the identification of molecules that block the growth and proliferation of new vessels.
Angiogenesis can be characterized by the invasion, migration, and proliferation of both smooth muscle and endothelial cells. A vast variety of growth factors have been identified that promote this neovascularization. For example, beta fibroblast growth factor (bFGF) is a heparin-binding cationic endothelial cell growth factor that is angiogenic in many tissues . Receptors for bFGF have been identified in myoblasts and endothelial cells . These receptors stimulate and promote endothelial cell proliferation and angiogenesis . Furthermore, bFGF is a potent regulator of developmental proliferation, migration, and differentiation of endothelial (and neural) precursor cells .
Developmentally, bFGF activity is highly regulated and has 10 times greater activity in mesenchymal tissue (blood vessels, endothelium, myoblasts) than in ectodermal tissue (neurons) [17,18]. Furthermore this molecule is a member of a diverse group of macromolecules that are ubiquitous on mammalian cell surfaces, extracellular matrix, and basal lamina. Beta fibroblast growth factor binds to basal lamina via heparin-like molecules, which protect against proteolytic degradation of the receptors. (For a review of this topic, readers are directed to reference 19.) Other receptor molecules that are structurally related to bFGF and are endothelial growth factors include ectodermal growth factor, (ECGF), acidic fibroblast growth factor (aFGF), and transforming growth factor-alpha (TGF-alpha). This is just one family of molecules that contribute to endothelial and vascular proliferation.
Other Molecules Also Important
The issue is even more complicated because a family of vascular adhesion molecules also play a role in these processes . For example, during wound healing, basement membranes of blood vessels express several adhesion proteins (fibrin, fibronectin, and others), and the integrin family of adhesion molecule receptors are expressed
on smooth muscles and endothelial cells [4-12]. These integrins lead to endothelial cell migration and neovascularization.
Other molecules have a vascular-promoting potential. For example, neural regeneration of the facial and sciatic nerves after transectional injuries is promoted by nerve growth factor [20,21]. However, neovascularization precedes neural regeneration [19,20]. Thus, NGF may promote revascularization.
In summary, it appears that angiogenesis is a complex cascade of chemical reactions that play a role at different time sequences during development, wound healing, and vascular neogenesis in a variety of pathologic states.
In general, these macromolecules can be divided into two subgroups that are not mutually exclusive: The most common group of molecules studied are angiotrophic factors (eg, ECGF, EGF, bFGF, aFGF), which directly stimulate angiogenesis. The second category includes angiopromotive factors (laminin, fibrin, heparin, interferons, prostaglandins), which facilitate neovascularization [21,22].
In fact, the authors' use of steroids and interferon-alpha 2a (Roferon-A) is based on molecular biologic principles, especially the indirect effect of interferons on vascularization through their actions on prostaglandins. The association of Kasabach-Merritt syndrome with consumptive coagulopathies should further be studied, with particular focus on platelets and their heparin-like binding proteins, as well as the resultant hypoxia in the afflicted area. (Oxygen deprivation is a strong factor in neovascularization). Thus, it appears that what the authors categorize as a problem of classification is more complex and more interesting.
Does it seem fortuitous that the neonatal induction, growth, and involution of hemangiomas should parallel so nicely other models of vascular proliferation? It seems most probable that endothelial- and smooth muscle-stimulating molecules, such as bFGF and integrins (and many others), play a role here. Observed from this perspective, lymphatic malformations (cystic hygromas) and capillary cutaneous lesions (capillary malformations) may not be different disease entities from hemangiomas (based on molecular biologic criteria), since both continue to grow and proliferate in the vast majority of cases (Figure 3).
The concept of the "sick dermatome," based on an autonomic neural deficiency to the cutaneous venous plexus, as a cause of venous ectasia (hence, a port-wine stain) seems of dubious validity and is doomed to the dustbin of history. Does neural denervation in neck dissections lead to cutaneous venous ectasia? Cutaneous tumor invasion and radiation therapy do cause cutaneous venous changes! Why? In the face of hypoxia and venous stasis, what is the effect of oxygen-free radicals on neovascularization and endothelial proliferation?
In conclusion, the authors present the current state of treatment of vascular congenital lesions of the head and neck region. This approach is ablative and cosmetic in nature and is not grounded in a sound scientific foundation, but rather, is based on personal experience and literature review. The main focus is on gross anatomy and accessibility. The classification system described, therefore, has many problems and flaws. It is most assuredly incorrect in the long run.
Furthermore, a taxonomy should enhance and expand understanding of disease states and lead toward future research and potential cures. The proposed classification fails to do this! As it stands, this classification is not particularly helpful. However, on an interim basis, this review denotes the current state of affairs in the definition and treatment of congenital vascular lesions of the head and neck region.
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